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A Preclinical Study on Brugada Syndrome with a CACNB2 Variant Using Human Cardiomyocytes from Induced Pluripotent
Rujia Zhong1, Theresa Schimanski1,2, Feng Zhang1
1First Department of Medicine, Faculty of Medicine, University Medical Centre Mannheim (UMM), University of Heidelberg, 68167 Mannheim, Germany.
Abstract:
Aims: Some gene variants in the sodium channels, as well as calcium channels, have been associated with Brugada syndrome (BrS). However, the investigation of the human cellular phenotype and the use of drugs for BrS in presence of variant in the calcium channel subunit is still lacking. Objectives: The objective of this study was to establish a cellular model of BrS in the presence of a CACNB2 variant of uncertain significance (c.425C > T/p.S142F) using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and test drug effects using this model. Methods and results: This study recruited cells from a patient with Brugada syndrome (BrS) and recurrent ventricular fibrillation carrying a missense variant in CACNB2 as well as from three healthy independent persons. These cells (hiPSC-CMs) generated from skin biopsies of healthy persons and the BrS patient (BrS-hiPSC-CMs) as well as CRISPR/Cas9 corrected cells (isogenic control, site-variant corrected) were used for this study. The hiPSC-CMs from the BrS patient showed a significantly reduced L-type calcium channel current (ICa-L) compared with the healthy control hiPSC-CMs. The inactivation curve was shifted to a more positive potential and the recovery from inactivation was accelerated. The protein expression of CACNB2 of the hiPSC-CMs from the BrS-patient was significantly decreased compared with healthy hiPSC-CMs. Moreover, the correction of the CACNB2 site-variant rescued the changes seen in the hiPSC-CMs of the BrS patient to the normal state. These data indicate that the CACNB2 gene variant led to loss-of-function of L-type calcium channels in hiPSC-CMs from the BrS patient. Strikingly, arrhythmia events were more frequently detected in BrS-hiPSC-CMs. Bisoprolol (beta-blockers) at low concentration and quinidine decreased arrhythmic events. Conclusions: The CACNB2 variant (c.425C > T/p.S142F) causes a loss-of-function of L-type calcium channels and is pathogenic for this type of BrS. Bisoprolol and quinidine may be effective for treating BrS with this variant.
Insights
A CACNB2 gene variant causes Brugada syndrome (BrS) by reducing calcium channel function in heart cells. Low-dose bisoprolol and quinidine may effectively treat this BrS type.
Area of Science:
- Cardiology
- Genetics
- Stem Cell Biology
Background:
- Brugada syndrome (BrS) is linked to sodium and calcium channel gene variants.
- The cellular phenotype and drug efficacy for BrS with calcium channel variants remain understudied.
Purpose of the Study:
- To create a cellular model of BrS using patient-derived cardiomyocytes with a CACNB2 variant.
- To investigate the functional impact of the CACNB2 variant and test potential drug treatments.
Main Methods:
- Generated human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a BrS patient with a CACNB2 variant and healthy controls.
- Utilized CRISPR/Cas9 gene editing to create isogenic controls.
- Assessed L-type calcium channel current (ICa-L), channel kinetics, and protein expression.
Main Results:
- BrS hiPSC-CMs exhibited significantly reduced ICa-L, altered inactivation curves, and accelerated recovery from inactivation.
- CACNB2 protein expression was decreased in BrS hiPSC-CMs; correction restored normal function.
- BrS hiPSC-CMs showed increased arrhythmia events, which were reduced by low-dose bisoprolol and quinidine.
Conclusions:
- The CACNB2 c.425C > T/p.S142F variant causes L-type calcium channel loss-of-function, confirming its pathogenicity in BrS.
- Low-dose bisoprolol and quinidine show potential as therapeutic agents for BrS associated with this CACNB2 variant.
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